Many important drugs have poor oral bioavailability because they are poorly soluble in water. Many approaches have been suggested to overcome this problem. Although some approaches have been used, with limited commercial success, each approach has its own drawbacks and limitations.
In one approach, a water-soluble prodrug of a poorly water-soluble drug is made [1-4]. The prodrug approach is limited to those molecules that have functionality amenable to facile removal in the body to form the drug. Not all poorly water-soluble drugs are so endowed. Furthermore, the prodrug would likely be considered a new chemical entity and require separate approval from regulatory agencies, adding considerable time and cost to bringing the product to market.
The bioavailability of poorly water-soluble drugs has been improved by decreasing the particle size of the drug to increase the surface area. Milling [5-6], high pressure homogenization [7-8], spray drying [9], lyophilization of solutions in water organic solvent mixtures [10], and lyophilization of solutions inorganic solvents [11-12] have been tried. Size reduction is, in principal, generally applicable for improving bioavailability, but achieving size reduction by, for example, high energy milling, requires special equipment and is not always applicable. High pressure homogenization requires special equipment and requires organic solvents that can remain in the comminuted product. Spray drying also requires solvents and generally produces particles that are too large.
Lyophilization is usually limited to materials that are soluble in water in any event, although there have been some efforts at using organic solvents.
The solubility of poorly soluble antibiotics has been improved by complexation with polymers or cyclodextrins. Polymer complexes have been formed with PVP in organic solvent [13a], or with PVP in heated water [13]. Other drugs have been complexed with cyclodextrins and polymers [14-15].
The bioavailability of poorly soluble drugs has been improved by dispersing the drug in a soluble polymer, often with addition of surfactants [16-24].
Some combinations of techniques have shown added improvement. For example spraying and drying a dispersion of drug and polymer or cyclodextrin on pellets in a fluidized bed dried [25-26]. The combination of solid dispersion and lyophilization to improve solubility has been demonstrated [27], and the use of solid dispersions absorbed on a carrier having a large surface area has also been demonstrated [28].
Clearly, there is a need for a simpler and generally applicable means of making and delivering particles of drugs having a size below 10 μm and especially below 1 μm.
Many of the above-described techniques require forming particles by solvent removal which, in turn, entails concentration of a solution. During solution concentration, solute molecules, which in solution are statistically separated into individual molecules and small clusters or aggregates, are drawn together to form larger molecular aggregates. When the solute drug eventually precipitates, relatively larger crystals are formed.
Lyophilization (freeze drying) has the advantage of allowing the solvent to be removed whilst keeping the solute relatively immobile, thereby suppressing enlargement of clusters or aggregates. When the solvent is removed, the formed crystals are smaller or the material is amorphous, reflecting the separation of the molecules in the frozen solution state. Molecular separation can be improved and aggregate formation still further suppressed by lyophilizing a more dilute solution, although one pays a hefty price in energy requirements for removing more solvent. Lyophilization is usually a very slow, energy intensive process and usually requires high vacuum equipment. Furthermore, there is a tendency for the crystals formed to aggregate in the free state, undoing the job that the freeze drying did. This tendency can sometimes be overcome with additives, but these must be compatible with the entire system.
Amorphous or nanoparticulate materials tend to show poor bulk flow properties as powders, requiring formulation work to be able to fill them into capsules. While these problems are not insurmountable, they add further limitations in the usefulness of the system. Many of the existing limitations are overcome by the present invention.